Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM.

PURPOSE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.

An evaluation of Rezafungin: the latest treatment option for adults with candidemia and invasive candidiasis.

INTRODUCTION: Invasive fungal infections, especially candidemia and invasive candidiasis, continue to cause substantial morbidity and mortality. In addition, the emergence of drug-resistant Candida species, notably C. glabrata and C. auris, along with limitations in available treatments, highlights the urgent need for novel, effective antifungal agents. AREAS COVERED: This review discusses the results of in vitro studies evaluating the spectrum and highlights the pharmacokinetic/pharmacodynamic properties. It also includes discussions on two key clinical studies that assess safety, tolerability, and efficacy. EXPERT OPINION: Rezafungin has demonstrated comparable efficacy to other echinocandins in two clinical studies and exhibits in vitro activity against a broad range of Candida species and Aspergillus spp. It has a favorable safety profile with minimal side effects, and no drug interactions or effects on QT intervals. In contrast to other echinocandins, it demonstrates dose-dependent killing, a prolonged half-life, and low clearance make it suitable for once-weekly dosing, which is supported by clinical trials confirming its efficacy. Rezafungin offers a promising option for the outpatient management of difficult to treat fungal infections. It has become a valuable addition to the antifungal arsenal, with the potential to reduce hospital length of stay and hospitalization costs and combat drug-resistant Candida species.

Efficacy of biofilm disrupters against Candida auris and other Candida species in monomicrobial and polymicrobial biofilms.

Candida species are now considered global threats by the CDC and WHO. Candida auris specifically is on the critical pathogen threat list along with Candida albicans. In addition, it is not uncommon to find Candida spp. in a mixed culture with bacterial organisms, especially Staphylococcus aureus producing polymicrobial infections. To eradicate these organisms from the environment and from patient surfaces, surface agents such as chlorhexidine (CHD) and Puracyn are used. Biofilm disrupters (BDs) are novel agents with a broad spectrum of antimicrobial activity and have been used in the management of chronic wounds and to sterilise environmental surfaces for the past several years. The goal of this study was to evaluate BDs (BlastX, Torrent, NSSD) and CHD against Candida spp. and S. aureus using zone of inhibition assays, biofilm and time-kill assays. All BDs and CHD inhibited C. auris growth effectively in a concentration-dependent manner. Additionally, CHD and the BDs showed excellent antimicrobial activity within polymicrobial biofilms. A comparative analysis of the BDs and CHD against C. auris and C. albicans using biofilm kill-curves showed at least 99.999% killing. All three BDs and CHD have excellent activity against different Candida species, including C. auris. However, one isolate of C. auris in a polymicrobial biofilm assay showed resistance/tolerance to CHD, but not to the BDs. The fungicidal activity of these novel agents will be valuable in eradicating surface colonisation of Candida spp, especially C. auris from colonised environmental surfaces and from wounds in colonised patients.

Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials.

BACKGROUND: Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. FINDINGS: ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups. INTERPRETATION: Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. FUNDING: Melinta Therapeutics and Cidara Therapeutics.

Clinical safety and efficacy of novel antifungal, fosmanogepix, for the treatment of candidaemia: results from a Phase 2 trial.

BACKGROUND: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration. METHODS: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (<96 h of treatment start) composed the modified intent-to-treat (mITT) population. Primary efficacy endpoint was treatment success at the end of study treatment (EOST) as determined by the Data Review Committee. Success was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at the EOST. RESULTS: Treatment success was 80% (16/20, mITT; EOST) and Day 30 survival was 85% (17/20; 3 deaths unrelated to fosmanogepix). Ten of 21 (48%) were switched to oral fosmanogepix. Fosmanogepix was well tolerated with no treatment-related serious adverse events/discontinuations. Fosmanogepix had potent in vitro activity against baseline isolates of Candida spp. (MICrange: CLSI, 0.002-0.03 mg/L). CONCLUSIONS: Results from this single-arm Phase 2 trial suggest that fosmanogepix may be a safe, well-tolerated, and efficacious treatment for non-neutropenic patients with candidaemia, including those with renal impairment.

Current oral hygiene and recreational behavioral trends in HIV disease.

OBJECTIVE: HIV disease is evolving with more HIV+ persons experiencing a high quality of life with well-controlled viremia. We recently enrolled a large cohort of HIV+ and clinically relevant HIV- persons for oral microbiome analyses that included a questionnaire related to oral hygiene and recreational behaviors. Here, the questionnaire responses were analyzed for behavioral trends within the cohort, together with trends over time by comparison to a previous geographically centered HIV+ cohort. METHODS: Data were collected by questionnaire at baseline visits as cross-sectional assessments. Multivariable analyses were conducted for associations of HIV status as well as age, race, and sex, on oral hygiene/recreational behaviors. RESULTS: HIV+ subjects had reduced brushing frequency, but increased incidence of past cleanings and frequency of dry mouth, compared to the HIV- subjects. Within the entire cohort, positive associations were identified between age and several oral hygiene practices, and between age, race, and sex for several recreational behaviors. In comparison to the historical cohort, the contemporary HIV+ cohort participated in fewer high-risk behaviors, but with similar trends for smoking and oral hygiene practices. CONCLUSION: HIV status had little association with oral hygiene and recreational behaviors despite several differences in age, race, and sex. Behavioral trends over time support a higher quality of life in people currently living with HIV.

Renewable Carbon Materials as Electrodes for High-Performance Supercapacitors: From Marine Biowaste to High Specific Surface Area Porous Biocarbons.

Waste, in particular, biowaste, can be a valuable source of novel carbon materials. Renewable carbon materials, such as biomass-derived carbons, have gained significant attention recently as potential electrode materials for various electrochemical devices, including batteries and supercapacitors. The importance of renewable carbon materials as electrodes can be attributed to their sustainability, low cost, high purity, high surface area, and tailored properties. Fish waste recovered from the fish processing industry can be used for energy applications and prioritizing the circular economy principles. Herein, a method is proposed to prepare a high surface area biocarbon from glycogen extracted from mussel cooking wastewater. The biocarbon materials were characterized using a Brunauer-Emmett-Teller surface area analyzer to determine the specific surface area and pore size and by scanning electron microscopy coupled with energy-dispersive X-ray analysis, Raman analysis, attenuated total reflectance Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and transmission electron microscopy. The electrochemical characterization was performed using a three-electrode system, utilizing a choline chloride-based deep eutectic solvent (DES) as an eco-friendly and sustainable electrolyte. Optimal time and temperature allowed the preparation of glycogen-based carbon materials, with a specific surface area of 1526 m2 g-1, a pore volume of 0.38 cm3 g-1, and an associated specific capacitance of 657 F g-1 at a current density of 1 A g-1, at 30 °C. The optimal material was scaled up to a two-electrode supercapacitor using a DES-based solid-state electrolyte (SSE@DES). This prototype delivered a maximum capacitance of 703 F g-1 at a 1 A g-1 of current density, showing 75% capacitance retention over 1000 cycles, delivering the highest energy density of 0.335 W h kg-1 and power density of 1341 W kg-1. Marine waste can be a sustainable source for producing nanoporous carbon materials to be incorporated as electrode materials in energy storage devices.

Double resonance between corner states in distinct higher-order topological phases.

Recent studies have shown that higher-order topologies in photonic systems lead to a robust enhancement of light-matter interactions. Moreover, higher-order topological phases have been extended to systems even without a band gap, as in Dirac semimetals. In this work, we propose a procedure to simultaneously generate two distinctive higher-order topological phases with corner states that allow a double resonant effect. This double resonance effect between the higher-order topological phases, was obtained from the design of a photonic structure with the ability to generate a higher-order topological (HOTI) insulator phase in the first bands and a higher-order Dirac half-metal phase (HODSM). Subsequently, using the corner states in both topological phases, we tuned the frequencies of both corner states such that they were separated in frequency by a second harmonic. This idea allowed us to obtain a double resonance effect with ultra-high overlap factors, and a considerable improvement in the nonlinear conversion efficiency. These results show the possibility of producing a second-harmonic generation with unprecedented conversion efficiencies in topological systems with simultaneous HOTI and HODSM phases. Furthermore, since the corner state in the HODSM phase presents an algebraic 1/rdecay, our topological system can be helpful in experiments about the generation of nonlinear Dirac-ligh-matter interactions.

Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris: Results from a Phase 2 Trial.

Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. In vitro susceptibility of Candida isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent in vitro activity against all C. auris isolates (MIC range: 0.008 to 0.015 µg/mL [CLSI]; 0.004-0.03 µg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.

Independent Effects of HIV and Antiretroviral Therapy on the Oral Microbiome Identified by Multivariate Analyses.

The oral microbiome is an important predictor of health and disease. We recently reported significant yet modest effects of HIV under highly active antiretroviral therapy (ART) on the oral microbiome (bacterial and fungal) in a large cohort of HIV-positive (HIV+) and matched HIV-negative (HIV-) individuals. As it was unclear whether ART added to or masked further effects of HIV on the oral microbiome, the present study aimed to analyze the effects of HIV and ART independently, which also included HIV- subjects on preexposure prophylaxis (PrEP) therapy. Cross-sectional analyses of the effect of HIV devoid of ART (HIV+ ART- versus matched HIV- subjects) showed a significant effect on both the bacteriome and mycobiome (P < 0.024) after controlling for other clinical variables (permutational multivariate analysis of variance [PERMANOVA] of Bray-Curtis dissimilarity). Cross-sectional analyses evaluating the effects of ART (HIV+ ART+ versus HIV+ ART- subjects) revealed a significant effect on the mycobiome (P < 0.007) but not the bacteriome. In parallel longitudinal analyses, ART (before versus after the initiation of ART) had a significant effect on the bacteriome, but not the mycobiome, of HIV+ and HIV- PrEP subjects (P < 0.005 and P < 0.016, respectively). These analyses also revealed significant differences in the oral microbiome and several clinical variables between HIV- PrEP subjects (pre-PrEP) and the HIV-matched HIV- group (P < 0.001). At the species level, a small number of differences in both bacterial and fungal taxa were identified within the effects of HIV and/or ART. We conclude that the effects of HIV and ART on the oral microbiome are similar to those of the clinical variables but collectively are modest overall. IMPORTANCE The oral microbiome can be an important predictor of health and disease. For persons living with HIV (PLWH), HIV and highly active antiretroviral therapy (ART) may have a significant influence on their oral microbiome. We previously reported a significant effect of HIV with ART on both the bacteriome and mycobiome. It was unclear whether ART added to or masked further effects of HIV on the oral microbiome. Hence, it was important to evaluate the effects of HIV and ART independently. For this, multivariate cross-sectional and longitudinal oral microbiome analyses (bacteriome and mycobiome) were conducted within the cohort, including HIV+ ART+ subjects and HIV+ and HIV- (preexposure prophylaxis [PrEP]) subjects before and after the initiation of ART. While we report independent significant effects of HIV and ART on the oral microbiome, we conclude that their influence is similar to that of the clinical variables but collectively modest overall.

Chitins from Seafood Waste as Sustainable Porous Carbon Precursors for the Development of Eco-Friendly Supercapacitors.

Carbon materials derived from marine waste have been drawing attention for supercapacitor applications. In this work, chitins from squid and prawn marine wastes were used as carbon precursors for further application as electrodes for energy storage devices. Chitins were obtained through a deproteinization method based on enzymatic hydrolysis as an alternative to chemical hydrolysis as commonly presented in the literature. The obtained porous carbons were characterized using a BET surface area analyzer to determine the specific surface area and pore size, as well as scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), Raman spectroscopy, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), to characterize their morphology, composition, and structure. The electrochemical characterization was performed using a glassy carbon (GC) electrode modified with marine waste-based porous carbons as the working electrode through cyclic voltammetry and galvanostatic charge/discharge using ethaline, a choline chloride-based deep eutectic solvent (DES), as an eco-friendly and sustainable electrolyte. Squid and prawn chitin-based carbons presented a surface area of 149.3 m2 g-1 and 85.0 m2 g-1, pore volume of 0.053 cm3 g-1 and 0.029 cm3 g-1, and an associated specific capacitance of 20 and 15 F g-1 at 1 A g-1, respectively. Preliminary studies were performed to understand the effect of -OH groups on the chitin-based carbon surface with DES as an electrolyte, as well as the effect of aqueous electrolytes (1 mol L-1 sulphuric acid (H2SO4) and 1 mol L-1 potassium hydroxide (KOH)) on the capacitance and retention of the half-cell set up. It is provided, for the first time, the use of chitin-based carbon materials obtained through a one-step carbonization process combined with an eco-friendly DES electrolyte for potential application in energy storage devices.

Cell-Laden Marine Gelatin Methacryloyl Hydrogels Enriched with Ascorbic Acid for Corneal Stroma Regeneration.

Corneal pathologies from infectious or noninfectious origin have a significant impact on the daily lives of millions of people worldwide. Despite the risk of organ rejection or infection, corneal transplantation is currently the only effective treatment. Finding safe and innovative strategies is the main goal of tissue-engineering-based approaches. In this study, the potential of gelatin methacryloyl (GelMA) hydrogels produced from marine-derived gelatin and loaded with ascorbic acid (as an enhancer of the biological activity of cells) was evaluated for corneal stromal applications. Marine GelMA was synthesized with a methacrylation degree of 75%, enabling effective photocrosslinking, and hydrogels with or without ascorbic acid were produced, encompassing human keratocytes. All the produced formulations exhibited excellent optical and swelling properties with easy handling as well as structural stability and adequate degradation rates that may allow proper extracellular matrix remodeling by corneal stromal cells. Formulations loaded with 0.5 mg/mL of ascorbic acid enhanced the biological performance of keratocytes and induced collagen production. These results suggest that, in addition to marine-derived gelatin being suitable for the synthesis of GelMA, the hydrogels produced are promising biomaterials for corneal regeneration applications.

Synthesis of gold decorated silica nanoparticles and their photothermal properties.

Silica-Gold Nanostructures (SGNs), composed of a silica core decorated by gold nanoparticles, have the photothermal capacity to transform near-infrared (NIR) wavelengths into heat. This work presents a simple, efficient, and replicable method of synthesis of SGNs and their characterization by: (1) transmission electron microscopy to obtain micrographs of the particles and their corresponding diameter distribution; (2) diffraction patterns showing the amorphous atomic arraignment of the silica and the crystalline atomic arrangement of the gold nanoparticles; (3) zeta potential confirming the stability of the SGNs in a colloidal solution; and (4) thermal images displaying the capacity of SGNs to convert NIR irradiation into heat and their respective increment in temperature. SGNs were synthesized over silica cores with diameters of 63, 83, and 132 nm and decorated with a partial gold shell. They were heated with a coherent light intensity of 340 mW/cm2 with a wavelength of 852 nm. This wavelength is within the range of the optical window of the human body; therefore, SGNs may be used for the photothermal ablation of tumors with no damage to the tissue. The heating of different dimensions of SGNs took 6-8 min of NIR radiation, and their cooling, once the laser was turned off, was in the order of 2-3 min. It was found that SGNs, with a core diameter of 132 nm, have a notable photothermal capacity. That enables them to increase the temperature of their surroundings by 4.4 ºC. This increment in temperature is sufficient to induce cellular necrosis, which makes SGNs a good option for photothermal treatments.

Antitumor activity of copper(II) complexes with Schiff bases derived from N'-tosylbenzene-1,2-diamine.

The electrochemical oxidation of anodic metal copper in a solution of the ligands N-[(5-tert-butyl-2-hydroxyphenyl)methylidine]-N'-tosylbenzene-1,2-diamine [H2L1] and N-[(3,5-di-tert-butyl-2-hydroxyphenyl)methylidine]-N'-tosylbenzene-1,2-diamine, [H2L2] afforded homoleptic [CuL] compounds or solvate [CuLS] complexes. The addition to the electrochemical cell of coligands (L') such as 2,2'-bipyridine (2-bpy), 4,4'-bipyridine(4-bpy) or 1,10-phenanthroline (phen) allowed the synthesis, in one step, of heteroleptic [CuLL'] compounds, namely [CuL1(H2O)] (1), [CuL1(2,2'-bpy)]⋅CH3CN (2), [CuL1(phen)]·H2O (3), [Cu2L12(4,4'-bpy)] (4), [CuL2(CH3OH)] (5), [CuL2(2,2'-bpy)] (6), [CuL2(phen)] (7) and [Cu2L22(4,4'-bpy)] (8). The crystal structures of both ligands, H2L1, H2L2, and those of the complexes (2), (4), (5), (6) and (7) have been determined by X-ray diffraction techniques. Coordination polyhedron around metal atom is square planar for [CuL2(CH3OH)] (5) and [Cu2L12(4,4'-bpy)] (4) and square pyramid for the other complexes with additional chelating ligands. The cytotoxic activity of this new series of copper(II) complexes against the SH-SY5Y neuroblastoma cell line and U87-MG and U373-MG glioblastoma cell lines has been investigated. Most of the test compounds showed higher activity than cisplatin in the three cell lines. Among this series, compound [CuL1(phen)] (3) displayed the highest activity with IC50 equal to 1.77 µM on SH-SY5Y whereas compound [Cu2L12(4.4'-bpy)] (4) resulted the most potent compounds on U87 MG and U373 MG glioblastoma cell lines. Studies on the cytotoxic activity of these derivatives suggest that these compounds induce cell death by a mechanism other than apoptosis.

Metastasis of melanoma in non-sentinel nodes in patients with metastatic sentinel node. Can we avoid complementary lymphadenectomy?

BACKGROUND: Lymph mapping with sentinel node biopsy is the standard procedure for lymph node staging in patients with cutaneous melanoma with a tumor thickness of 1 mm or greater. Patients who have metastases in sentinel node must undergo complementary lymphadenectomy; however, it has not been shown to improve survival. OBJECTIVE: To know the prevalence in our setting of metastases in the product of complementary lymphadenectomy in patients with metastatic sentinel node. METHOD: Evaluation of a descriptive, retrospective, observational and analytical cohort of patients with metastatic sentinel node submitted to lymphadenectomy. Multivariate analysis of tumor thickness, neural invasion, location, sentinel node number, serum DHL level, lymph nodes dissected and extracapsular spread. RESULTS: 67 patients, 35 women and 32 men with a mean of 66 years, 22% had metastases in lymph nodes from complementary lymphadenectomy, 19% of them with extracapsular spread; no relationship with the Breslow level. Extracapsular spread in the sentinel node, lymphadenectomy time, and perineural invasion in the primary tumor were prognostic factors for non-sentinel node metastasis. CONCLUSIONS: In this series, 22% of the patients with a sentinel node-positive have metastases in the non-sentinel nodes, 19% of them with extracapsular spread, which justifies complementary lymphadenectomy.

ANTECEDENTES: El mapeo linfático con biopsia del ganglio centinela es el procedimiento estándar de estadificación ganglionar en pacientes con melanoma cutáneo con grosor tumoral de 1 mm o mayor. Los pacientes que tienen metástasis en él deben ser sometidos a linfadenectomía complementaria; sin embargo, esta no ha mostrado mejorar la superviviencia. OBJETIVO: Conocer la prevalencia en nuestro medio de metástasis en el producto de linfadenectomía complementaria en pacientes con ganglio centinela metastásico. MÉTODO: Evaluación de una cohorte descriptiva, retrospectiva, observacional y analítica de pacientes con ganglio centinela metastásico sometidos a linfadenectomía, con análisis multivariado de grosor tumoral, invasión neural, localización, número de ganglios centinela, concentración sérica de deshidrogenasa láctica, ganglios disecados en linfadenectomía y ruptura capsular. RESULTADOS: Hubo 67 pacientes (35 mujeres y 32 hombres), con una media de 66 años de edad, en el 22% hubo metástasis en ganglios de linfadenectomía complementaria y en el 19% ruptura capsular; sin relación con el nivel de Breslow. La ruptura capsular en el ganglio centinela, el tiempo de linfadenectomía y la invasión perineural fueron factores pronóstico de metástasis en ganglios no centinela. CONCLUSIONES: En esta serie, el 22% de los pacientes tuvieron metástasis en ganglios no centinela, el 19% de ellos con ruptura capsular, lo cual justifica la linfadenectomía complementaria.

Of Fears and Budgets: Strategies of Control in Vespa velutina Invasion and Lessons for Best Management Practices.

Implementing management practices for the control of invasive species can be a complex task with multiple dimensions, where the identification of stakeholders and drivers of those practices is of paramount importance. The invasive hornet Vespa velutina has spread across Europe and Asia from its native range in SE Asia in recent years. A common control method is the removal and destruction of its nests on citizens' request to call centers. In this paper we have explored the knowledge and main factors that influence the perceptions of the citizens on the species in an invaded municipality in NW Spain, as well as the management practices of the municipal emergency unit responsible for nest removal activities. Our analysis brings out multiple drivers of management practices that derive both from the citizens' and practitioners' knowledge, and highlights several points of conflict between both stakeholder groups connected to (1) the degree of service provided to the local population, (2) the risk of allergic reactions as a motive to urge removals, or (3) the quality of information provided by mass media. Our results support the crucial importance of environmental education programs that seek to increase the knowledge of the general public about the threats of invasive species. Such programs might be incorporated to implement and optimize management plans of V. velutina by enhancing communication between experts and local population.

Multifunctional PLA/Gelatin Bionanocomposites for Tailored Drug Delivery Systems.

A series of bionanocomposites composed of shark gelatin hydrogels and PLA nanoparticles featuring different nanostructures were designed to generate multifunctional drug delivery systems with tailored release rates required for personalized treatment approaches. The global conception of the systems was considered from the desired customization of the drug release while featuring the viscoelastic properties needed for their ease of storage and posterior local administration as well as their biocompatibility and cell growth capability for the successful administration at the biomolecular level. The hydrogel matrix offers the support to develop a direct thermal method to convert the typical kinetic trapped nanostructures afforded by the formulation method whilst avoiding the detrimental nanoparticle agglomeration that diminishes their therapeutic effect. The nanoparticles generated were successfully formulated with two different antitumoral compounds (doxorubicin and dasatinib) possessing different structures to prove the loading versatility of the drug delivery system. The bionanocomposites were characterized by several techniques (SEM, DLS, RAMAN, DSC, SAXS/WAXS and rheology) as well as their reversible sol-gel transition upon thermal treatment that occurs during the drug delivery system preparation and the thermal annealing step. In addition, the local applicability of the drug delivery system was assessed by the so-called "syringe test" to validate both the storage capability and its flow properties at simulated physiological conditions. Finally, the drug release profiles of the doxorubicin from both the PLA nanoparticles or the bionanocomposites were analyzed and correlated to the nanostructure of the drug delivery system.

Kinetics of Bacterial Adaptation, Growth, and Death at Didecyldimethylammonium Chloride sub-MIC Concentrations.

Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) are standard indexes for determining disinfection effectiveness. Nevertheless, they are static values disregarding the kinetics at sub-MIC concentrations where adaptation, growth, stationary, and death phases can be observed. The understanding of these dynamic mechanisms is crucial to designing effective disinfection strategies. In this study, we studied the 48 h kinetics of Bacillus cereus and Escherichia coli cells exposed to sub-MIC concentrations of didecyldimethylammonium chloride (DDAC). Two mathematical models were employed to reproduce the experiments: the only-growth classical logistic model and a mechanistic model including growth and death dynamics. Although both models reproduce the lag, exponential and stationary phases, only the mechanistic model is able to reproduce the death phase and reveals the concentration dependence of the bactericidal/bacteriostatic activity of DDAC. This model could potentially be extended to study other antimicrobials and reproduce changes in optical density (OD) and colony-forming units (CFUs) with the same parameters and mechanisms of action.

Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability.

The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARS-CoV-2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-α), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-to-patient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients. IMPORTANCE Lung vascular endothelial injury in SARS-CoV-2 patients is one of the most important causes of morbidity and mortality and has been linked to more severe complications including acute respiratory distress syndrome (ARDS) and subsequent death due to multiorgan failure. We have demonstrated that in eight consecutive patients with SARS-CoV-2, who were not selected for evidence of endothelial injury, the diluted plasma-induced intense lung microvascular damage, in vitro. Known endothelial barrier-disruptive agents and proposed mediators of increased endothelial permeability in SARS-CoV-2, induced changes in permeability that were smaller in magnitude and shorter in duration than plasma from patients with SARS-CoV-2. The effect on endothelial cell permeability of plasma from patients with SARS-CoV-2 was heat-labile. The main plasma factor that causes the increased endothelial permeability remains to be identified. Our study provides a possible approach for future studies to understand the underlying mechanisms leading to vascular injury in SARS-CoV-2 infections.